Project description:The total synthesis of anticancer marine natural product lehualide B is described. Overall, the synthesis proceeds in just eight steps from a simple gamma-pyrone, does not require the use of protecting groups, and delivers each nonconjugated trisubstituted alkene with high levels of stereoselection. The challenging C12-C16 bis-trisubstituted 1,4-diene was installed with a complex reductive cross-coupling reaction between a preformed Ti-alkyne complex and a pyrone-containing allylic alcohol.
Project description:The enantioselective total synthesis of pironetin has been achieved in 11 steps from known aldehyde 2. The synthesis relies on the formation of 5 out of 6 stereocenters through titanium mediated iterative aldol reactions. Key steps in this synthesis include an acetal aldol reaction to establish the stereochemistry at C8 and C9, an acetate aldol reaction, and "Evans" syn aldol reaction.
Project description:Zearalenone, a fungal macrocyclic polyketide, is a member of the resorcylic acid lactone family. Herein, we characterize in vitro the thioesterase from PKS13 in zearalenone biosynthesis (Zea TE). The excised Zea TE catalyzes macrocyclization of a linear thioester-activated model of zearalenone. Zea TE also catalyzes the cross coupling of a benzoyl thioester with alcohols and amines. Kinetic characterization of the cross coupling is consistent with a ping-pong bi-bi mechanism, confirming an acyl-enzyme intermediate. Finally, the substrate specificity of the Zea TE indicates the TE may help control iterative cycling on PKS13 by rapidly offloading the final resorcylate-containing product.
Project description:A total synthesis of the mitochondrial complex I inhibitor piericidin A1 is described. It features a unique strategy for the key disconnection, highlighting a modified Negishi carboalumination/Ni-catalyzed cross-coupling on a polyenyne precursor.
Project description:The Suzuki-Miyaura cross-coupling is one of the most often utilized reactions in the synthesis of pharmaceutical compounds and conjugated materials. In its most common form, the reaction joins two sp(2)-functionalized carbon atoms to make a biaryl or diene/polyene unit. These substructures are widely found in natural products and small molecules and thus the Suzuki-Miyaura cross-coupling has been proposed as the key reaction for the automated assembly of such molecules, using protecting group chemistry to affect iterative coupling. We present herein, a significant advance in this approach, in which multiply functionalized cross-coupling partners can be employed in iterative coupling without the use of protecting groups. To accomplish this, the orthogonal reactivity of different boron substituents towards the boron-to-palladium transmetalation reaction is exploited. The approach is illustrated in the preparation of chiral enantioenriched compounds, which are known to be privileged structures in active pharmaceutical compounds.
Project description:An efficient total synthesis of the annulated indole natural product (±)-cis-trikentrin B was accomplished by means of a regioselectively generated 6,7-indole aryne cycloaddition via selective metal-halogen exchange from a 5,6,7-tribromoindole. The unaffected C-5 bromine was subsequently used for a Stille cross-coupling to install the butenyl side chain and complete the synthesis. This strategy provides rapid access into the trikentrins and the related herbindoles, and represents another application of this methodology to natural products total synthesis. The required 5,6,7-indole aryne precursor was prepared using the Leimgruber-Batcho indole synthesis.
Project description:Efficient access to chiral C(sp(3)) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp(3)) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable ?-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp(3)-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp(3)) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.
Project description:Abietane diterpenes and miltirone series have shown important activities and for medical purposes in order to achieve the total synthesis of 1-oxomiltrone 1 and miltirone 4, a versatile intermediate 6 was found. The compound 6 could be used as a precursor A-B-C rings with different oxidative degrees in selected abietane diterpenes when synthesized through high yield Suzuki reaction and subsequent cyclization, and total synthesis of 1-oxomiltirone (1) has been achieved. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s13659-013-0034-7 and is accessible for authorized users.
Project description:A concise (9-step) synthesis of the tropoloisoquinoline alkaloid pareitropone has been achieved starting from 2-bromoisovanillin. The key step features oxidative cyclization of a readily available phenolic nitronate for the convenient construction of the fused tropone ring. This work underscores the synthetic utility of intramolecular oxidative coupling reactions of phenolic nitronates.
Project description:A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross-coupling trimerizations. With this method, the natural product pyrolaside B was synthesized for the first time. The key strategy used for this novel synthesis is the facile one-step construction of a spiroketal trimer intermediate, which can be selectively reduced to give the natural product framework without recourse to stepwise Ullmann- and Suzuki-type couplings. As a result, pyrolaside B can be obtained expeditiously in five steps and 16 % overall yield. Three other analogues were synthesized, thus highlighting the utility of the method, which provides new accessibility to this area of chemical space. A novel xanthene was also synthesized through controlled Lewis acid promoted rearrangement of a spiroketal trimer.